Low Antibody Response Seen with RA Drug

Action Points

Few patients with rheumatoid arthritis (RA) treated with abatacept, either with or without concomitant methotrexate, developed immunogenic responses to the biologic agent that could interfere with efficacy and safety.

Clinically meaningful improvements also were seen after 18 months in 53.8% of the combination group (subcutaneous abatacept plus methotrexate) and in 88.6% of those who received subcutaneous abatacept alone.

Few rheumatoid arthritis (RA) patients treated with abatacept -- with concomitant methotrexate or not -- developed immunogenic responses that could interfere with efficacy and safety of the biologic agent, a phase II, international, open-label study found.

Among 100 patients receiving subcutaneous abatacept (Orencia), two receiving it as monotherapy developed transient and low-titer antibodies during the first 4 months of therapy, as did two who also were given methotrexate, according to Peter Nash, MD, of the University of Queensland in Brisbane, Australia, and colleagues.

At the conclusion of the 4-month randomized phase of the trial, none of the patients in either group were antibody positive, the researchers reported in the May Arthritis Care & Research.

Immunogenic responses can occur with the administration of biologic agents when antibodies develop and block the molecular binding of the compound with its target. Immunosuppressive drugs such as methotrexate are often given to prevent this and are required for the use of some biologics such as infliximab (Remicade).

However, up to one-quarter of patients are unable to take methotrexate.

Abatacept is a T-cell costimulation modulator that is indicated for use either with or without methotrexate in RA patients who have not responded to methotrexate alone.

To examine the potential immunogenicity of abatacept, and to see if concomitant methotrexate influenced this, Nash and colleagues enrolled 51 patients who were already taking methotrexate and 49 who either had never taken methotrexate or had stopped the drug.

Subcutaneous abatacept was administered once weekly as a fixed dose of 125 mg.

During the 4-month initial phase, patients in both groups could take anti-inflammatory drugs and low-dose oral corticosteroids.

After the initial 4-month phase of the trial, patients in the monotherapy group were allowed to add methotrexate and dosages were adjusted at the local investigator's discretion, with follow-up continuing for an additional 20 months.

Patients' mean age was 53, disease duration averaged 10 years, and more than three-quarters were women.

A total of 96% completed the initial phase and 83% remained on treatment at 2 years.

During the long-term phase, 23% of those in the monotherapy group began taking methotrexate, and one patient in the combination group discontinued the drug.

In only one case of seropositivity was there a concomitant adverse event, which consisted of mild-to-moderate rash and paresthesias.

"No further association between immunogenicity and safety was observed, and immunogenicity was not association with [subcutaneous] injection reactions," the investigators noted.

Injection site reactions were seen only in 5.9% and 8.2% of the combination and monotherapy groups, respectively.

In contrast, injection site reactions have been observed in 6% to 20% of patients receiving the anti-tumor necrosis factor agents.

Serious adverse events in the initial phase of the trial included Pneumocystis jiroveci pneumonia or syncope in two patients in the combination group and a lower respiratory tract infection and cartilage injury, one each, in monotherapy patients.

During the long-term phase, 13 patients experienced serious adverse events such as bronchopneumonia and four discontinued treatment because of adverse events.

One case of basal cell carcinoma occurred during follow-up, and one case of mild autoimmune thyroiditis was seen.

The investigators also reported on clinical efficacy for the treatment throughout 2 years, although this was a secondary endpoint.

Within 2 weeks of beginning treatment, disease activity scores had fallen in both groups, with reductions of 0.4 and 0.7 points in the combination and monotherapy groups, respectively.

After 4 months, clinically meaningful decreases on disease activity scores were seen in 62.5% (95% CI 49.2 to 75.8) of the combination group and in 66.7% (95% CI 53.5 to 79.9) of the monotherapy group.

Clinically meaningful improvements also were seen after 18 months in 53.8% (95% CI 38.2 to 69.5) of the combination group and in 88.6% (95% CI 78 to 99.1) of the monotherapy group.

In the combination group, 48.9% had low disease activity and 6.4% were in remission by month 4, while the equivalent numbers in the monotherapy group were 44.2% and 11.6%, respectively.

In addition, remission rates after 18 months were 15% and 36.1% in the combination and monotherapy groups.

With regard to the mean 28-joint Disease Activity Score (DAS28) changes were 1.67 for combination therapy and 1.94 for monotherapy at month 4. For those in the long-term phase, mean DAS28 changes from baseline were 1.84 for the combination and 2.86 for monotherapy at month 18.

"These findings are in contrast to immunogenicity with other biologic agents, which can be associated with treatment discontinuation due to inefficacy and failure to sustain disease activity reductions," the researchers wrote.

Unlike other abatacept studies, this trial did not include the use of an intravenous loading dose at treatment initiation, so that the influence of methotrexate on immunogenicity would be clearer.

The rapid response to treatment suggests that the loading dose may not be needed, they noted.

"The safety and efficacy benefits observed with [subcutaneous] abatacept monotherapy in the absence of an IV loading dose are relevant observations for clinical practice, particularly for those patients who cannot receive [methotrexate] because of tolerability issues and those patients whose medical history precludes administration of IV abatacept," they stated.

Limitations to the study included its open-label design and small numbers of patients.

The study was supported by Bristol-Myers Squibb.

Several of the investigators are employees of Bristol-Myers Squibb.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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